Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10](SC)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C([C:36](OO)=[O:37])C=1.S(=O)(O)[O-].[Na+].C[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10]([O:37][CH3:36])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Agent: C[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
62.8 mg (0.153 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of dichloromethane. 52.7 mg (0.305 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of methanol and excessive amounts of 295 mg (1.53 mmol) of sodium methoxide (28% methanol solution) was added at room temperature and stirred at 60° C. for 6 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[N+:31]([O-:33])=[O:32])[CH2:16][CH2:15]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[N+:31]([O-:33])=[O:32])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: Cc1ccc(OCCCN2CCC(O)CC2)c([N+](=O)[O-])c1
Reactant: ClC(c1ccsc1)c1ccsc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: Cc1ccc(OCCCN2CCC(OC(c3ccsc3)c3ccsc3)CC2)c([N+](=O)[O-])c1

Procedure:
The procedure of Example 36 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(3-thienyl)methoxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1.[C:25](=O)(ON1C(=O)CCC1=O)[O:26]N1C(=O)CCC1=O>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25](=[O:26])[NH:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:13][CH:12]=1
Reactant: Nc1cncnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cncnc2n1-c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of N4-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyrimidine-4,5-diamine (55 mg) and bis(2,5-dioxopyrrolidin-1-yl) carbonate (53 mg) in DMF (5 mL) was stirred overnight at 80° C. then at 95° C. for 3 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), 5% aqueous lithium chloride (50 mL) then brine (50 ml), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 methanol/methylene chloride), solvent exchanged with acetonitrile and freeze dried from acetonitrile/water to afford 9-[4-(1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8-one (19 mg) as off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([OH:14])[N:11]([CH3:15])[N:10]=1.[OH-].[Na+].[CH2:18]=O.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([S:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([CH2:18][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:29])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[C:12]([OH:14])[N:11]([CH3:15])[N:10]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: Cn1nc(-c2ccc(Cl)cc2Cl)cc1O
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Cc2c(-c3ccc(Cl)cc3Cl)nn(C)c2O)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
3-(2,4-Dichlorophenyl)-5-hydroxy-1-methylpyrazole (1.3 g (5 mmol)) synthesized in Reference Example 6 and 0.3 g (7.5 mmol) of sodium hydroxide were dissolved in 5 mL of ethanol. While stirring the resulting solution at room temperature, 1.0 g (11 mmol) of a 35% formalin solution was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Subsequently, 0.9 g (5 mmol) of sodium p-toluenesulfinate was charged thereto at room temperature, and the obtained mixture was stirred for 2 hours. After the reaction, 2.5 g (25 mmol) of 35% hydrochloric acid was added dropwise thereto, 15 mL of water was further added, and the precipitated crystal was collected by filtration, washed twice with 10 mL of water and dried by a hot air drier to obtain 2.1 g (yield: 90.3%) of the title compound as a pale yellow crystal.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[CH:20]=[C:19]([CH3:29])[C:18]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:12][CH:11]=1)[CH:6]([CH3:8])[CH3:7])C.[OH-].[Na+].CCO>C1COCC1>[CH3:13][O:16][C:17]1[CH:26]=[C:21]([CH2:22][CH:23]([OH:27])[CH3:24])[CH:20]=[CH:19][CH:18]=1.[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH:9]=[C:5]([CH:6]([CH3:8])[CH3:7])[C:4]([OH:36])=[O:3])=[CH:15][CH:14]=1)=[C:18]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:19]([CH3:29])=[CH:20]2
Reactant: CCOC(=O)C(=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(C=C(C(=O)O)C(C)C)cc3)c(-c3ccccc3)c(C)cc2c1
Product: COc1cccc(CC(C)O)c1
Yield: 505.3 %

Procedure:
Using the procedure described in Example 31 (Step 4), isomer (1) of 2-[4-(6-Methoxy-3-methyl-2-phenyl-naphthalen-1-yloxy)-benzylidene]-3-methyl-butyric acid ethyl ester (222-1) (0.159 g, 0.331 mmol), 1 N NaOH (4 mL), EtOH (3 mL) and THF (3 mL) afforded isomer (1) (223-1) 0.139 g (93%) of the title compound. 1H NMR (400 MHz, d-CDCl3): δ 1.22 (d, J=7.0 Hz, 6H), 2.23 (s, 3H), 3.08-3.15 (m, 1H), 3.93 (s, 3H), 6.58 (d, J=8.6 Hz, 2H), 7.04-7.07 (m, 3H), 7.12-7.13 (m, 3H), 7.20-7.28 (m, 4H), 7.54 (d, J=13.4, 2H), 7.76 (d, J=9.1 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:27]=[CH:26][C:25]([P:28](Cl)(Cl)=[O:29])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:15]([C:22]1[CH:27]=[CH:26][C:25]([P:28]2(=[O:29])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1ccc(Oc2ccccc2)cc1
Product: O=P1(c2ccc(Oc3ccccc3)cc2)c2ccccc2CN1c1ccccc1

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 4-phenoxyphenyl phosphonic dichloride. The reaction of the dilithio compound and the 4-phenoxyphenyl phosphonic dichloride was conducted at 0° C. The crude product produced as a result of the chromatographic separation was distilled at 140° C. and the resulting residue was crystallilzed from diethyl ether to yield 1-(4-phenoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as beige needles. A second crop was obtained to give a total yield of 0.75 g, 3% yield of 1-(4-phenoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 207°-208° C. and the following analysis:
Reaction SMILES: [Na+].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1Cl)NC(=O)CN2
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A solution of N-(4'-chloro-5'-methyl-2'-nitrophenyl)glycine sodium salt (0.300 g, 1.23 mmol, as prepared above) and tin (II) chloride dihydrate (0.830 g, 3.68 mmol, Aldrich, used as received) in ethanol (4.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the precipitated solid was filtered, washed with ethanol (1.0 mL) and dried under vacuum to yield 0.160 g (66%) of the title compound as a yellow powder; 1H NMR (DMSO-d6): δ2.099 (s, 3H), 3.655 (s, 2H), 6.037 (s, 1H), 6.538 (s, 1H), 6.685 (s, 1H), 10.241 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:68]([SH:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:75][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:4][C:3]=1/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)/C=C(/C)c1cc(Br)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)/C=C(/C)c1cc(SCc2ccccc2)ccc1N
Temperature: 90 °C
Reaction time: 36 h
Yield: 58 %

Procedure:
A solution of (Z)-ethyl 3-(2-amino-5-bromophenyl)but-2-enoate (3.3817 g, 11.90 mmol), xantphos (1.033 g, 1.785 mmol), pd2(dba)3 (0.545 g, 0.595 mmol), and n,n-diisopropylethylamine (6.24 ml, 35.7 mmol) in 24 mL dioxane was heated to 80° C. then was treated with benzyl mercaptan (2.252 ml, 19.04 mmol). After stirring for 36 hours, an additional portion of xantphos (1.033 g, 1.785 mmol), pd2(dba)3 (0.545 g, 0.595 mmol), and n,n-diisopropylethylamine (6.24 ml, 35.7 mmol) was added, and the reaction mixture was heated to 90° C. overnight. The reaction mixture was then poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave (Z)-ethyl 3-(2-amino-5-(benzylthio)phenyl)but-2-enoate (2.26 g, 6.90 mmol, 58.0% yield). m/z (ESI) 328.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].BrC[CH2:12][CH2:13][O:14][CH3:15].[C:16](#N)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:12][CH:13]([O:14][CH3:15])[CH3:16]
Reactant: COCCCBr
Reactant: Oc1ccc(F)cc1Br
Reactant: CC#N
Product: COC(C)COc1ccc(F)cc1Br
Yield: 88 %

Procedure:
2-Bromo-4-fluorophenol (950 mg, 4.97 mmol) and 1-bromo-3-methoxypropane (1000 mg, 6.53 mmol) in acetonitrile (10 ml) was treated as for preparation 62 to afford crude title compound as a yellow oil (1.16 g, 88%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:43]=[CH:42][C:20]([C:21]([NH:23][CH:24]([C:32]2[NH:36][C:35]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:34]=3[N:33]=2)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:22])=[CH:19][C:18]=1[Cl:44])=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[NH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:43]=[CH:42][C:20]([C:21]([NH:23][CH:24]([C:32]2[NH:36][C:35]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:34]=3[N:33]=2)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:22])=[CH:19][C:18]=1[Cl:44])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1C(=O)c1ccc(C(=O)NC(Cc2ccccn2)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCC1CCCN1C(=O)c1ccc(C(=O)NC(Cc2ccccn2)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 17 from 4-[2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]-3-chloro-N-[1-(5-chloro-1H-benzimidazol-2-yl)-2-(pyridin-2-yl)ethyl]benzamide and trifluoroacetic acid. Yield: 216 mg (85%, mixture of four stereoisomers); Rf value: 0.27 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C27H26Cl2N6O2 (537.45); mass spectrum: (M−H)−=535/537/539 (chlorine isotope).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][CH3:21])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: COc1ccccc1N
Product: COc1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 86.6 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.442 mmol) and o-methoxyaniline (76 mg, 0.62 mmol) to give 170 mg of the title compound (86%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 9.27 (s, 1H), 7.88 (d, 1H, J=8.1 Hz), 7.24 (s, 1H), 7.17 (s, 1H), 7.08 (t, 1H, J=8.1 Hz), 7.03 (d, 1H, J=8.1 Hz), 6.90 (t, 1H, J=8.1 Hz), 5.16~5.27 (m, 1H), 3.81 (s, 3H), 3.12 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.81 (dm, 1H, J =17.1 Hz), 2.77 (dd, 1H, J=13.5, 10.8 Hz), 2.62 (dd, 1H, J=13.5, 5.4 Hz), 2.11 (dm, 1H, J=13.5 Hz), 1.77~1.95 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15](C=O)=[N:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:36][C:37]([O:39][CH3:40])=[O:38])C=CC=CC=1.[CH2:53](Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15](/[CH:53]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[N:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(C=O)nc2)cc1
Reactant: ClCCl
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a solution of 5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)picolinaldehyde (0.265 g, 0.68 mmol) in DCM (3.38 mL) at 0° C. was added methyl 2-(triphenylphosphoranylidene)acetate (0.543 g, 1.63 mmol) and the reaction was stirred at room temperature for 18 h. Upon completion the mixture was concentrated in vacuo to afford crude material which was purified by column chromatography (SiO2, 0-25% EtOAc/heptanes) to afford (E)-methyl 3-(5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate (96 mg, 0.22 mmol, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm=3.70-3.75 (m, 6H), 3.79-3.83 (m, 3 H), 6.70 (d, J=15.66 Hz, 1 H), 6.77-6.88 (m, 3 H), 7.02 (dd, J=8.59, 3.03 Hz, 1 H), 7.17 (s, 1 H), 7.18-7.22 (m, 2 H), 7.48-7.59 (m, 3 H), 8.42 (d, J=2.53 Hz, 1 H). LC/MS (m/z, MH+): 448.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:11][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[N:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[Cl-].[NH4+]>O.[Fe]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:12]2[O:11][C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[N:14][N:13]=2)=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(OCc2nnc(Nc3ccc(Cl)c(Cl)c3)o2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(OCc2nnc(Nc3ccc(Cl)c(Cl)c3)o2)cc1
Yield: 86.7 %

Procedure:
To a stirred solution of N-(3,4-dichlorophenyl)-5-((4-nitrophenoxy)methyl)-1,3,4-oxadiazol-2-amine (150 mg, 0.394 mmol) in water (20 mL)/methanol (20 mL), ammonium chloride (211 mg, 3.94 mmol) and iron powder (176 mg, 3.15 mmol) were added and heated to reflux for 4 hours. The reaction mixture was passed though Celite. Solvent was removed under vacuum to obtain 5-((4-aminophenoxy)methyl)-N-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-amine (0.12 g, 87%). 1H NMR: 400 MHZ, DMSO-d6: δ 5.16 (s, 2H), 5.60 (bs, 2H), 6.62 (d, J=8.40 Hz, 2H), 6.82 (dd, J=2.00, 6.80 Hz, 2H), 7.48 (dd, J=2.40, 8.80 Hz, 1H), 7.61 (d, J=8.80 Hz, 1H), 7.89 (d, J=2.80 Hz, 1H), 11.00 (s, 1H). LCMS: RT 1.66 min. LCMS (ES-API), m/z 351.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[C:17](Cl)(Cl)=[S:18].O.[NH2:22][NH2:23]>C(OCC)C.O.ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:3]=1[NH:4][C:17]([NH:22][NH2:23])=[S:18]
Reactant: S=C(Cl)Cl
Reactant: CC(C)c1cccc(F)c1N
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cccc(F)c1NC(=S)NN
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a 100 mL round-bottomed flask equipped with a stir bar and nitrogen inlet were added 2-fluoro-6-isopropylaniline (0.415 g, 2.71 mmol), dichloromethane (13.6 mL), water (6.78 mL), and sodium bicarbonate (0.683 g, 8.13 mmol). To this biphasic mixture was added thiophosgene (0.199 mL, 2.60 mmol) and the reaction was stirred vigorously for 2 hours. The suspension was filtered through a phase separator cartridge and the organic phase was concentrated in a 100 mL round-bottomed flask. The flask was equipped with a magnetic stir bar and nitrogen inlet and the residue was dissolved in ethanol (6.78 mL). To the resulting solution was added hydrazine hydrate (0.131 mL, 2.71 mmol) and the reaction was stirred at room temperature for 2 days. The solution was concentrated and the resulting residue was suspended in a mixture of diethyl ether and hexanes and reconcentrated to give a solid. The solid was suspended in a minimal amount of diethyl ether and the mixture was diluted with hexanes. The majority of the diethyl ether was evaporated and the resulting solid was collected by vacuum filtration, washed with hexanes and then dried under house vacuum to provide the title compound (0.518 g, 2.28 mmol, 84% yield) as a white solid: mp 122-124° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (bs, 1H), 7.52 (bs, 1H), 7.32 (td, J=8.1, 5.6 Hz, 1H), 7.17-7.12 (m, 1H), 7.00 (ddd, J=9.5, 8.2, 1.4 Hz, 1H), 4.07 (bs, 2H), 3.15 (hept, J=7.0 Hz, 1H), 1.24 (d, J=6.9 Hz, 6H); ESIMS m/z 229 ([M+H]+).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C(=O)(O)[O-].[Na+].Cl[C:15]([O:17][CH3:18])=[O:16].Cl>C(OCC)C.O>[OH:4][C@H:3]([CH3:5])[C@H:2]([NH:1][C:15]([O:17][CH3:18])=[O:16])[C:6]([OH:8])=[O:7]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.1 %

Procedure:
L-Threonine (0.50 g, 4.2 mmol) and sodium bicarbonate (1.13 g, 13.4 mmol) were dissolved into water (20 mL) then cooled in an ice bath. Methyl chloroformate (0.36 mL, 4.62 mmol) was dissolved in diethyl ether (2 mL) and added dropwise with vigorous stirring. The solution was stirred at ambient temperature for 5 hours then adjusted to pH 3 with concentrated hydrochloric acid and extracted into ethyl acetate. The organic solution was dried over sodium sulfate, filtered, and concentrated to give 0.12 g of the title compound as a waxy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].C(N(CC)CC)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[CH3:19][N:20]([CH3:25])[S:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([O:5][CH2:6][C:7]#[N:8])[CH:3]=1)(=[O:23])=[O:22]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#CCOc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-aminophenoxy)-acetonitrile (1.5 g, from Example 1), triethylamine (3.22 mL) in THF (35 mL) was added dimethylsulfamoyl chloride (4.2 mL) dropwise over 10 min. After stirring at room temperature for 1 hr, the solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with 5% HCl solution and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel eluting with ethyl acetate:dichloromethane (10:90) to give N,N-dimethyl-N'-(3-cyanomethoxyphenyl)-sulfamide (1.11 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[NH2:27][C:28]1([CH2:31][OH:32])[CH2:30][CH2:29]1>>[OH:32][CH2:31][C:28]1([NH:27][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:25])[CH2:30][CH2:29]1
Reactant: NC1(CO)CC1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: N#Cc1ccc2c(c1)cc(C(=O)NC1(CO)CC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and (1-amino-cyclopropyl)methanol in a manner similar to that described in Example 11.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1>CCCCCC.O1CCCC1>[C:13]([C:5]([CH3:6])([CH3:7])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:14]([CH3:16])([C:13]([O:18][CH3:19])=[O:17])[CH3:15])=[CH:24][CH:23]=1)([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)C
Reactant: CC(C)NC(C)C
Reactant: BrCc1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1ccc(CC(C)(C)C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To 1 liter of dry tetrahydrofuran was added 52 g of diisopropylamine. The mixture was cooled to -78° C and 325 ml of 1.6 M n-butyllithium in hexane was added. After 1 hour of stirring 52 g of methyl isobutyrate was added dropwise followed by stirring for another 30 minutes. Then 63 g of α,α'-dibromo-p-xylene was slowly added. The reaction mixture was stirred overnight and brought to room temperature. The mixture was filtered and solvent was removed from the filtrate by evaporation. The residue was recrystallized from methanol to obtain 63 g of 1,4-bis(2-carbomethoxy-2-methylpropyl)benzene, m.p. 74°-76° C.